Preeclampsia is a major cause of maternal and fetal mortality and morbidity, and is a disease unique to human beings during pregnancy. Recent evidence has indicated that preeclampsia is characterized by placental maladaptation and body-wide endothelial cell injury. Failure of trophoblastic invasion into myometrial segments of maternal spiral arteries and the production of cytotoxic mediators which cause systemic endothelial damage also seem to be implicated.
Trophoblasts are a unique cell type in that they share characteristics of both normal and neoplastic tissue. During normal development, like neoplastic cells, human trophoblasts invade through the extracellular matrix into the myometrial portion of spiral arteries. However, unlike neoplastic cells which endlessly invade and finally spread to other organs, the invasive properties of the trophoblasts are eventually brought under control, further cell differentiation proceeds and cell senescence occurs. In normal gestation, trophoblasts convert spiral arteries into uteroplacental arteries by the above process. Pijnenborg et al., in Trophoblast Research (Denker and Aplin, eds.) Plenum Press, New York, p. 33 (1990). Uteroplacental arteries then dilate approximately 30-fold as large as the spiral arteries. Resulting hemodynamic changes enable the placental bed to satisfy the increased demand for oxygen from the fetus during the latter stages of gestation. In preeclamptic women, however, spiral arteries are not properly converted into uteroplacental arteries due to the failure of the second wave of trophoblastic migration into the myometrium at the beginning of the second trimester. Khong et al., Br. J. Obstet. Gynecol., 93:1049-1059 (1986). As a result, preeclamptic women typically demonstrate a high-resistance, high-pressure, and low-flow state with intact, non-dilated spiral arteries, Robertson et al., Am. J. Obstet. Gynecol., 155:401-412 (1986), and demonstrate a wide variety of clinical syndromes. Therefore, abnormal behavior of the fetus-derived trophoblast appears to be a central aspect of the disease.
Cytokines provide an important communication system in coordinating immune and inflammatory responses. Among the cytokines are a number of colony stimulating factors (CSFs), which are named for their major target cells, including granulocyte (G-CSF), granulocyte-macrophage (GM-CSF) and macrophage (M-CSF, also known as CSF-1) colony stimulating factors. Other cytokines include the interleukins, including IL-1 through IL-13, which are known to possess varying activities including being involved in hematopoiesis, and providing defenses against pathogenic infections.
Cytokines are produced in the uterus and placenta during normal pregnancy. Tabibzadeh, Endocrine Reviews, 12:272-290 (1991). In rats, it has been observed that M-CSF is secreted by uterine gland cells, and the levels increased approximately one thousand-fold in the first few days of pregnancy, with the novel receptor present on invasive trophoblast cells. Pollard et al., Nature, 330:484-486 (1987); Uzumaki et al., PNAS, USA, 86:9323-9326 (1989). In humans, the expression and localization of mRNA for M-CSF have been demonstrated in mesenchymal cells of the chorionic villous stroma, particularly in cytotrophoblasts lining the villous core and in the cytotrophoblastic core in the first trimester; in villous mesenchymal cells in the second trimester; and in cells lining the villous vessels in the third trimester. Kanazaki et al., Human Reprod., 7:563-567 (1992); Daiter et al., J. Clin. Endocrinol. Metab. 74:850-858 (1992). Circulating levels of macrophage M-CSF during pregnancy are also higher than those of non-pregnant women. Yong et al., Blood, 180:2897-2902 (1992).
Other cytokines have been identified in placenta and/or uterus. TNF-.alpha. is present in human amniotic fluids and supernatants of placental and decidual tissues. Jaattela et al., Lab. Invest. 58:48-52 (1988). Trophoblast derived TNF.alpha. induces release of human chorionic gonadotropin (hCG) using IL-6 and IL-6 receptor-dependent systems in normal human trophoblasts. Ying et al., J. Clin. Endocrinol. Metab., 74:184-191 (1992). Conversely, hCG and human placental lactogen (hPL) increase the expression of TNF.alpha.. Schafer et al., J. Perinat. Med., 20:233-240 (1992).